Mesenchymal stem cells promote mesenteric vasodilation through hydrogen sulfide and endothelial nitric oxide

Jan Te Winkel, Quincy E. John, Brian D. Hosfield, Natalie A. Drucker, Amitava Das, Ken R. Olson, Troy A. Markel

Research output: Contribution to journalArticle

Abstract

Mesenteric ischemia is a devastating process that can result in intestinal necrosis. Mesenchymal stem cells (MSCs) are becoming a promising treatment modality. We hypothesized that 1) MSCs would promote vasodilation of mesenteric arterioles, 2) hydrogen sulfide (H2S) would be a critical paracrine factor of stem cell-mediated vasodilation, 3) mesenteric vasodilation would be impaired in the absence of endothelial nitric oxide synthase (eNOS) within the host tissue, and 4) MSCs would improve the resistin-to-adiponectin ratio in mesenteric vessels. H2S was measured with a specific fluorophore (7-azido-3-methylcoumarin) in intact MSCs and in cells with the H2S-producing enzyme cystathionine β synthase (CBS) knocked down with siRNA. Mechanical responses of isolated second- and third-order mesenteric arteries (MAs) from wild-type and eNOS knockout (eNOSKO) mice were monitored with pressure myography, after which the vessels were snap frozen and later analyzed for resistin and adiponectin via multiplex beaded assay. Addition of MSCs to the myograph bath significantly increased vasodilation of norepinephrine-precontracted MAs. Knockdown of CBS in MSCs decreased H2S production by MSCs and also decreased MSC-initiated MA dilation. MSC-initiated vasodilation was further reduced in eNOSKO vessels. The MA resistin-to-adiponectin ratio was higher in eNOSKO vessels compared with wild-type. These results show that MSC treatment promotes dilation of MAs by an H2S-dependent mechanism. Furthermore, functional eNOS within the host mesenteric bed appears to be essential for maximum stem cell therapeutic benefit, which may be attributable, in part, to modifications in the resistin-to-adiponectin ratio.NEW & NOTEWORTHY Stem cells have been shown to improve survival, mesenteric perfusion, and histological injury scores following intestinal ischemia. These benefits may be due to the paracrine release of hydrogen sulfide. In an ex vivo pressure myography model, we observed that mesenteric arterial dilation improved with stem cell treatment. Hydrogen sulfide release from stem cells and endothelial nitric oxide synthase within the vessels were critical components of optimizing stem cell-mediated mesenteric artery dilation.

Original languageEnglish (US)
Pages (from-to)G441-G446
JournalAmerican journal of physiology. Gastrointestinal and liver physiology
Volume317
Issue number4
DOIs
StatePublished - Oct 1 2019

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Hydrogen Sulfide
Mesenchymal Stromal Cells
Vasodilation
Nitric Oxide
Mesenteric Arteries
Resistin
Nitric Oxide Synthase Type III
Adiponectin
Stem Cells
Dilatation
Myography
Cystathionine
Pressure
Stem Cell Factor
Arterioles
Therapeutics
Baths
Knockout Mice
Small Interfering RNA
Norepinephrine

Keywords

  • eNOS
  • hydrogen sulfide
  • mesenchymal stromal cells
  • mesenteric vessels
  • pressure myography

ASJC Scopus subject areas

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)

Cite this

Mesenchymal stem cells promote mesenteric vasodilation through hydrogen sulfide and endothelial nitric oxide. / Te Winkel, Jan; John, Quincy E.; Hosfield, Brian D.; Drucker, Natalie A.; Das, Amitava; Olson, Ken R.; Markel, Troy A.

In: American journal of physiology. Gastrointestinal and liver physiology, Vol. 317, No. 4, 01.10.2019, p. G441-G446.

Research output: Contribution to journalArticle

Te Winkel, Jan ; John, Quincy E. ; Hosfield, Brian D. ; Drucker, Natalie A. ; Das, Amitava ; Olson, Ken R. ; Markel, Troy A. / Mesenchymal stem cells promote mesenteric vasodilation through hydrogen sulfide and endothelial nitric oxide. In: American journal of physiology. Gastrointestinal and liver physiology. 2019 ; Vol. 317, No. 4. pp. G441-G446.
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